Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and mortality from COPD continues to increase. Long-term oxygen therapy has been shown to reduce mortality in COPD patients with severe hypoxemia and is one of the only treatments for COPD with a proven survival benefit. The Long-term Oxygen Treatment Trial (LOTT) is an NHLBI-sponsored clinical trial to determine whether COPD patients with moderate hypoxemia will benefit from continuous oxygen therapy. Results of earlier studies in moderately hypoxemic COPD patients suggest heterogeneity in the response to oxygen. In other diseases, pharmacogenetic influences on oxygen toxicity and on oxygen benefit have been demonstrated. However, the impact of pharmacogenetics on the response to oxygen therapy in COPD is unknown. The overall hypothesis is that a set of oxygen-responsive genes will be differentially expressed in COPD patients treated with supplemental oxygen and that inter-individual variation in these oxygen-responsive genes will predict change in exercise tolerance and disease-specific quality of life (QoL) in COPD patients treated with long-term oxygen therapy. To test this hypothesis, we will address three Specific Aims: 1) Genomic profiling of response to oxygen therapy: We will collect peripheral blood for RNA at baseline (pre- randomization) and at follow-up, and perform whole-genome gene expression profiling in 100 LOTT participants randomized to supplemental oxygen to define a set of genes that are significantly up- or down- regulated in response to oxygen therapy. We will test whether gene expression profiles predict change in exercise capacity and disease-specific QoL in response to long-term oxygen therapy. 2) Pharmacogenetics of long-term oxygen therapy: We will genotype linkage-disequilibrium tagging single nucleotide polymorphisms (SNPs) in 40-50 differentially expressed oxygen-responsive genes in 800 subjects randomized to supplemental oxygen and test for association with change in exercise capacity and disease-specific QoL in COPD patients treated with long-term oxygen therapy. We will also test whether these SNPs are associated with gene expression of the differentially expressed oxygen-responsive genes. 3) Replication of pharmacogenetic associations: For 120 SNPs significantly associated with change in exercise capacity disease-specific QoL in the initial 800 subjects, we will genotype a separate set of 1200 LOTT subjects to replicate genetic associations for response to long-term oxygen therapy. Significance: This study will further our understanding of the effects of supplemental oxygen in COPD and may allow for better prediction of patients most likely to benefit or most likely to be harmed by long-term oxygen therapy. PUBLIC HEALTH RELEVANCE: The Long-term Oxygen Treatment Trial (LOTT) Pharmacogenomics Ancillary Study will improve our understanding of the effects of treating chronic obstructive pulmonary disease (COPD) patients with supplemental oxygen. The information gained may eventually allow physicians to predict which COPD patients are most likely to benefit or most likely to be harmed by long-term oxygen therapy.